Role of Perceived Social Support in Adherence to Antihypertensives and Controlled Hypertension: Findings of a Community Survey from Urban Nepal.

Introduction: Social support is considered vital for effective management of chronic conditions, but its role in improving adherence to antihypertensive medication and control of hypertension in urban Nepal is unknown. We examined the role of social support in adherence to antihypertensives and controlled blood pressure to inform future interventions for hypertension management. Methods: We analyzed cross-sectional data collected at baseline of a cluster randomized trial of hypertension patients (n=1252) in the community between May and November 2022. Multidimensional scale of perceived social support was used to measure social support, adherence to antihypertensives was measured using the Morisky medication adherence scale -8, and individuals with systolic- and diastolic- blood pressure less than 140 and 90 mmHg respectively were considered to have controlled hypertension. Modified Poisson regression models were used to estimate the prevalence ratios and corresponding 95% confidence intervals. Results: We found that 914 (73%) individuals received moderate to high social support. Participants receiving high social support had a numerically lower proportion of controlled hypertension (51%) however not statistically significant. The proportion of good adherence to antihypertensives did not differ between the social support categories. There was no association in overall, family, friends, and significant other sub-scales of social support with controlled hypertension and adherence to antihypertensives. Discussion: Further studies to understand the quality and mechanisms through which social support contributes to blood pressure control are needed for the health system to include social support in designing and implementing community-based interventions for hypertension management.

Survival prediction in patients with gynecological cancer irradiated for brain metastases.

BACKGROUND AND PURPOSE: This large population-based, retrospective, single-center study aimed to identify prognostic factors in patients with brain metastases (BM) from gynecological cancers. MATERIAL AND METHODS: One hundred and forty four patients with BM from gynecological cancer treated with radiotherapy (RT) were identified. Primary cancer diagnosis, age, performance status, number of BM, presence of extracranial disease, and type of BM treatment were assessed. Overall survival (OS) was calculated using the Kaplan-Meier method and the Cox proportional hazards regression model was used for multivariable analysis. A prognostic index (PI) was developed based on scores from independent predictors of OS. RESULTS: Median OS for the entire study population was 6.2 months. Forty per cent of patients died within 3 months after start of RT. Primary cancer with the origin in cervix or vulva (p = 0.001),  Eastern Cooperative Oncology Group (ECOG) 3-4 (p < 0.001), and the presence of extracranial disease (p = 0.001) were associated with significantly shorter OS. The developed PI based on these factors, categorized patients into three risk groups with a median OS of 13.5, 4.0, and 2.4 months for the good, intermediate, and poor prognosis group, respectively. INTERPRETATION: Patients with BM from gynecological cancers carry a poor prognosis. We identified prognostic factors and developed a scoring tool to select patients with better or worse prognosis. Patients in the high-risk group have a particular poor prognosis, and omission of RT could be considered.

Overall Survival after Radiotherapy for Brain Metastases According to ECOG Status-A Prospective Study of 294 NSCLC Patients.

Up to 40% of non-smallcell lung cancer (NSCLC) patients develop brain metastases (BMs). The potential benefits of radiotherapy (RT) in patients with poor performance status (PS) are questionable, with considerable risk for futile treatment. We analyzed overall survival after initial radiotherapy in NSCLC patients with BMs, focusing on the relationship between PS and survival after RT. This study reports a prospective observational study including consecutive 294 NSCLC patients with first-time BMs. Overall survival (OS) was calculated from the start of RT to death or last follow-up (1 June 2023). Overall, in the 294 included patients (median age 69 years), the median OS was 4.6 months; 2.5 months after WBRT (n = 141), and 7.5 months after SRT (n = 153). After WBRT, mOS was equally poor for patients with ECOG 2 (1.9 months) and ECOG 3-4 (1.2 months). After SRT, mOS for patients with ECOG 2 was 4.1 months; for ECOG 3 patients, mOS was 4 1.6 months. For NSCLC patients with ECOG 2 diagnosed with BMs who are not candidates for surgery or SRT, WBRT should be questioned due to short survival.

Stroke and bleeding risk in atrial fibrillation with CHA2DS2-VASC risk score of one: the Norwegian AFNOR study.

BACKGROUND AND AIMS: The benefit of oral anticoagulant (OAC) therapy in atrial fibrillation (AF) and intermediate stroke risk is debated. In a nationwide Norwegian cohort with a non-sex CHA2DS2-VASc risk score of one, this study aimed to investigate (i) stroke and bleeding risk in AF patients with and without OAC treatment, and (ii) the risk of stroke in non-anticoagulated individuals with and without AF. METHODS: A total of 1 118 762 individuals including 34 460 AF patients were followed during 2011-18 until ischaemic stroke, intracranial haemorrhage, increased CHA2DS2-VASc score, or study end. One-year incidence rates (IRs) were calculated as events per 100 person-years (%/py). Cox regression models provided adjusted hazard ratios (aHRs [95% confidence intervals]). RESULTS: Among AF patients, the ischaemic stroke IR was 0.51%/py in OAC users and 1.05%/py in non-users (aHR 0.47 [0.37-0.59]). Intracranial haemorrhage IR was 0.28%/py in OAC users and 0.19%/py in non-users (aHR 1.23 [0.88-1.72]). Oral anticoagulant use was associated with an increased risk of major bleeding (aHR 1.37 [1.16-1.63]) but lower risk of the combined outcome of ischaemic stroke, major bleeding, and mortality (aHR 0.57 [0.51-0.63]). Non-anticoagulated individuals with AF had higher risk of ischaemic stroke compared to non-AF individuals with the same risk profile (aHR 2.47 [2.17-2.81]). CONCLUSIONS: In AF patients at intermediate risk of stroke, OAC use was associated with overall favourable clinical outcomes. Non-anticoagulated AF patients had higher risk of ischaemic stroke compared to the general population without AF with the same risk profile.

Digoxin Pharmacokinetics in Patients with Obesity Before and After a Gastric Bypass or a Strict Diet Compared with Normal Weight Individuals.

BACKGROUND AND OBJECTIVE: Several drugs on the market are substrates for P-glycoprotein (P-gp), an efflux transporter highly expressed in barrier tissues such as the intestine. Body weight, weight loss, and a Roux-en-Y gastric bypass (RYGB) may influence P-gp expression and activity, leading to variability in the drug response. The objective of this study was therefore to investigate digoxin pharmacokinetics as a measure of the P-gp phenotype in patients with obesity before and after weight loss induced by an RYGB or a strict diet and in normal weight individuals. METHODS: This study included patients with severe obesity preparing for an RYGB (n = 40) or diet-induced weight loss (n = 40) and mainly normal weight individuals scheduled for a cholecystectomy (n = 18). Both weight loss groups underwent a 3-week low-energy diet (<1200 kcal/day) followed by an additional 6 weeks of <800 kcal/day induced by an RYGB (performed at week 3) or a very-low-energy diet. Follow-up time was 2 years, with four digoxin pharmacokinetic investigations at weeks 0, 3, and 9, and year 2. Hepatic and jejunal P-gp levels were determined in biopsies obtained from the patients undergoing surgery. RESULTS: The RYGB group and the diet group had a comparable weight loss in the first 9 weeks (13 ± 2.3% and 11 ± 3.6%, respectively). During this period, we observed a minor increase (16%) in the digoxin area under the concentration-time curve from zero to infinity in both groups: RYGB: 2.7 µg h/L [95% confidence interval (CI) 0.67, 4.7], diet: 2.5 µg h/L [95% CI 0.49, 4.4]. In the RYGB group, we also observed that the time to reach maximum concentration decreased after surgery: from 1.0 ± 0.33 hours at week 3 to 0.77 ± 0.08 hours at week 9 (-0.26 hours [95% CI -0.47, -0.05]), corresponding to a 25% reduction. Area under the concentration-time curve from zero to infinity did not change long term (week 0 to year 2) in either the RYGB (1.1 µg h/L [-0.94, 3.2]) or the diet group (0.94 µg h/L [-1.2, 3.0]), despite a considerable difference in weight loss from baseline (RYGB: 30 ± 7%, diet: 3 ± 6%). At baseline, the area under the concentration-time curve from zero to infinity was -5.5 µg h/L [95% CI -8.5, -2.5] (-26%) lower in patients with obesity (RYGB plus diet) than in normal weight individuals scheduled for a cholecystectomy. Further, patients undergoing an RYGB had a 0.05 fmol/µg [95% CI 0.00, 0.10] (29%) higher hepatic P-gp level than the normal weight individuals. CONCLUSIONS: Changes in digoxin pharmacokinetics following weight loss induced by a pre-operative low-energy diet and an RYGB or a strict diet (a low-energy diet plus a very-low-energy diet) were minor and unlikely to be clinically relevant. The lower systemic exposure of digoxin in patients with obesity suggests that these patients may have increased biliary excretion of digoxin possibly owing to a higher expression of P-gp in the liver.

Facilitators and barriers to hypertension management in urban Nepal: findings from a qualitative study.

INTRODUCTION: In Nepal, one-fourth of the adult population has hypertension. Despite provision of comprehensive hypertension services through the primary healthcare system, huge gaps in treatment and control of hypertension exist. Our study explored the individual, interpersonal, health system and community-level barriers and facilitators affecting hypertension management in urban Nepal. METHODS: We used a qualitative methodology informed by Kaufman's socioecological model, conducting focus group discussions with hypertension patients and their family members. In-depth interviews with hypertension patients, healthcare providers and municipal officials were also conducted. RESULTS: We found that inadequate knowledge about hypertension and harmful cultural beliefs hindered effective treatment of hypertension. Interrupted medical supply and distrust in primary healthcare providers affected the poor's access to hypertension services. Poor communication between family members and gender norms affected adaptation of treatment measures. This study emphasised the role of family members in supporting patients in adhering to treatment measures and rebuilding community trust in primary healthcare providers for better access to hypertension services. The findings guided the development of a manual to be used by community health workers during home visits to support patients to control high blood pressure. CONCLUSION: The study highlights the importance of integrating various aspects of care to overcome the multiple barriers to hypertension management in urban settings in low-resource countries. Participatory home visits have the potential to empower individuals and families to develop and implement feasible and acceptable actions for home management of hypertension through improved adherence to antihypertensive medication, and behaviour change.

Preoperative Prognostic Index for Patients with Brain Metastases-A Population-Based Multi-Centre Study.

BACKGROUND: Brain metastases (BM) are common in cancer patients and are associated with high morbidity and mortality. Surgery is an option, but the optimal selection of patients for surgery is challenging and controversial. Current prognostication tools are not ideal for preoperative prognostication. By using a reference population (derivation data set) and two external populations (validation data set) of patients who underwent surgery for BM, we aimed to create and validate a preoperative prognostic index. METHODS: The derivation data set consists of 590 patients who underwent surgery for BM (2011-2018) at Oslo University Hospital. We identified variables associated with survival and created a preoperative prognostic index with four prognostic groups, which was validated on patients who underwent surgery for BM at Karolinska University Hospital and St. Olavs University Hospital during the same time period. To reduce over-fitting, we adjusted the index in accordance with our findings. RESULTS: 438 patients were included in the validation data set. The preoperative prognostic index correctly divided patients into four true prognostic groups. The two prognostic groups with the poorest survival outcomes overlapped, and these were merged to create the adjusted preoperative prognostic index. CONCLUSION: We created a prognostic index for patients with BM that predicts overall survival preoperatively. This index might be valuable in supporting informed choice when considering surgery for BM.

Cluster randomised trial to evaluate comprehensive approach to hypertension management in Nepal: a study protocol.

INTRODUCTION: Despite having effective approaches for hypertension management including use of antihypertensive medication, monitoring of blood pressure and lifestyle modification many people with hypertension in Nepal remain undetected and untreated. A comprehensive intervention which provides personalised counselling on lifestyle modification, medication adherence together with support for regular monitoring of blood pressure is expected to achieve well controlled blood pressure. METHODS AND ANALYSIS: This is a community-based, non-blinded, parallel group, two-arm cluster randomised controlled trial, with an allocation ratio of 1:1, conducted in Budhanilkantha municipality, Nepal. Ten health facilities and their catchment area are randomly allocated to either of the two arms. 1250 individuals aged 18 years and older with an established diagnosis of hypertension will be recruited. The intervention arm receives a comprehensive hypertension management package that includes blood pressure audit by health workers, home-based patient support by community health workers to engage patient and family members in providing tailored educational counselling on behavioural and lifestyle changes in addition to routine care. The control arm includes routine hypertension care. Trained enumerators will ensure consent and collect data. Outcome data on blood pressure, weight, waist and hip circumference will be measured and self-reported data on diet, lifestyle, medication adherence and hypertension knowledge will be registered at 11 months' follow-up. The change in outcome measures will be compared by intention to treat, using a generalised linear mixed model. A formative assessment will be conducted using semistructured interviews and focus group discussions to explore factors affecting hypertension management. A mix-method approach will be applied for process evaluation to explore acceptability, adoption, fidelity, feasibility and coverage. ETHICS AND DISSEMINATION: Ethics approval was obtained from Nepal Health Research Council (682/2021) and Regional Committee for Medical and Health Research Ethics, Norway (399479). The findings will be disseminated in peer-reviewed journal articles and with decision makers in Nepal.

Neither Gastric Bypass Surgery Nor Diet-Induced Weight-Loss Affect OATP1B1 Activity as Measured by Rosuvastatin Oral Clearance.

INTRODUCTION: Rosuvastatin pharmacokinetics is mainly dependent on the activity of hepatic uptake transporter OATP1B1. In this study, we aimed to investigate and disentangle the effect of Roux-en-Y gastric bypass (RYGB) and weight loss on oral clearance (CL/F) of rosuvastatin as a measure of OATP1B1-activity. METHODS: Patients with severe obesity preparing for RYGB (n = 40) or diet-induced weight loss (n = 40) were included and followed for 2 years, with four 24-hour pharmacokinetic investigations. Both groups underwent a 3-week low-energy diet (LED; < 1200 kcal/day), followed by RYGB or a 6-week very-low-energy diet (VLED; < 800 kcal/day). RESULTS: A total of 80 patients were included in the RYGB group (40 patients) and diet-group (40 patients). The weight loss was similar between the groups following LED and RYGB. The LED induced a similar (mean [95% CI]) decrease in CL/F in both intervention groups (RYGB: 16% [0, 31], diet: 23% [8, 38]), but neither induced VLED resulted in any further changes in CL/F. At Year 2, CL/F had increased by 21% from baseline in the RYGB group, while it was unaltered in the diet group. Patients expressing the reduced function SLCO1B1 variants (c.521TC/CC) showed similar changes in CL/F over time compared with patients expressing the wild-type variant. CONCLUSIONS: Neither body weight, weight loss nor RYGB per se seem to affect OATP1B1 activity to a clinically relevant degree. Overall, the observed changes in rosuvastatin pharmacokinetics were minor, and unlikely to be of clinical relevance.

How Did People with Prediabetes Who Attended the Diabetes Prevention Education Program (DiPEP) Experience Making Lifestyle Changes? A Qualitative Study in Nepal.

Diabetes can be prevented through lifestyle modification in the prediabetic phase. A group-based lifestyle intervention called 'Diabetes Prevention Education Program' (DiPEP) was tested recently in Nepal. The present study aimed to explore experiences of making lifestyle changes among people with prediabetes participating in the DiPEP. This qualitative study, with semi-structured interviews of 20 participants, was conducted 4-7 months following DiPEP intervention. Data analysis was performed by thematic analysis. The results included four themes, understanding that diabetes could be prevented, lifestyle changes made, hurdles to overcome, and experiencing benefits leading to sustained change. Some participants said they felt relieved to know that they had a chance to prevent diabetes. The participants talked mostly about making changes in diet (reducing carbohydrate intake) and physical activity (starting exercises). Obstacles mentioned included a lack of motivation and a lack of family support to implement changes. Experiencing benefits such as weight loss and reduced blood sugar levels were reported to lead them to maintain the changes they had made. Understanding that diabetes could be prevented was a key motivator for implementing changes. The benefits and hurdles experienced by the participants of the present study can be taken into consideration while designing lifestyle intervention programs in similar settings.

Effectiveness of a group-based Diabetes Prevention Education Program (DiPEP) in a population with pre-diabetes: a cluster randomised controlled trial in Nepal.

Background: Although several lifestyle intervention studies have been conducted in low/middle-income countries, there were no such studies in Nepal. Therefore, a group-based culturally tailored Diabetes Prevention Education Program (DiPEP) was conducted recently. The study aimed to evaluate the effect of DiPEP in glycated haemoglobin (HbA1c), weight, waist circumference, physical activity and diet among population with pre-diabetes. Method: A two-arm cluster randomised controlled trial was conducted in 12 clusters of two urban areas in Nepal. The DiPEP was a 6 month intervention (four 1-hour weekly educational sessions and 5 months of follow-up by community health workers/volunteers (CHW/Vs)). A postintervention assessment was done after 6 months. Linear mixed model was used to estimate the mean difference in primary outcome (HbA1c) and secondary outcomes (weight, waist circumference, physical activity and diet) between intervention and control arms, adjusted for baseline measure. Results: In intention-to-treat analysis with a total of 291 participants, the estimated mean difference in HbA1c was found to be 0.015 percentage point (95% CI -0.074 to 0.104) between the intervention arm and the control arm, while it was -0.077 (95% CI -0.152 to -0.002) among those who attended at least 3 out of 4 educational sessions. The estimated mean difference in weight (in participants who attended ≥1 educational session) was -1.6 kg (95% CI -3.1 to -0.1). A significantly lower grain consumption was found in intervention arm (-39 g/day, 95% CI -65 to -14) compared with the control arm at postintervention assessment. Conclusion: Although compliance was affected by COVID-19, individuals who participated in ≥3 educational sessions had significant reduction in HbA1c and those who attended ≥1 educational session had significant weight reduction. Grain intake was significantly reduced among the intervention arm than the control arm. Hence, group-based lifestyle intervention programmes involving CHW/vs is recommended for diabetes prevention. Trial registration number: NCT04074148.

Prevalence of prediabetes and associated factors of prediabetic stages: a cross-sectional study among adults in Nepal.

OBJECTIVES: To estimate the prevalence of prediabetes and to assess the association of prediabetic stages with sociodemographic, lifestyle and clinical factors DESIGN: Cross-sectional study at the screening and inclusion stage of a Diabetes Prevention Education Program (DiPEP) trial SETTING: The study was conducted in two urban communities in Nepal (October 2019-March 2020). PARTICIPANTS: A total of 6222 residents of two study sites, aged 18-64 years and without a history of diabetes, were eligible for prediabetes screening. Exclusion criteria were pregnancy, history of diabetes and critical illness. A total of 291 participants with prediabetes were included in this study. PRIMARY AND SECONDARY OUTCOME MEASURES: Prevalence of prediabetes based on glycated haemoglobin (HbA1c) criteria (5.7%-6.4%) was the primary outcome of the study. Odds Ratio and 95% CI were estimated to assess the associations between the outcome prediabetic stages (5.7%-5.9% vs 6.0%-6.4%) and sociodemographic, lifestyle and clinical factors in both unadjusted and adjusted models. RESULTS: Out of 6222 screened participants, 308 (5%, 95% CI: 4.4% to 5.5%) individuals were detected with prediabetes based on HbA1c. The mean age of 291 responded participants was 50.3±7.6 years and 67% were females. Among them, 78% aged 45-64 years, 97% had central obesity, 90% had high waist-hip ratio, 63% were hypertensive and 66% had no family history of diabetes. Approximately, 54% and 46% of individuals with prediabetes had HbA1c of 5.7%-5.9% and 6.0%-6.4%, respectively. Female gender was associated with prediabetes with HbA1c 6.0%-6.4% (OR, 1.98, 95% CI: 1.07 to 3.67) in the adjusted model. CONCLUSION: The estimated prevalence of prediabetes was 5% among screened participants, and female gender was associated with the prediabetic stage. As a large proportion of the population with prediabetes were not aware of their status, this study demonstrates a need for regular community screening programmes to detect individuals with prediabetes and provide them a comprehensive lifestyle intervention for diabetes prevention. TRIAL REGISTRATION NUMBER: NCT04074148, 2019/783.

Impact of type 2 diabetes on in vivo activities and protein expressions of cytochrome P450 in patients with obesity.

Previous studies have not accounted for the close link between type 2 diabetes mellitus (T2DM) and obesity when investigating the impact of T2DM on cytochrome P450 (CYP) activities. The aim was to investigate the effect of T2DM on in vivo activities and protein expressions of CYP2C19, CYP3A, CYP1A2, and CYP2C9 in patients with obesity. A total of 99 patients from the COCKTAIL study (NCT02386917) were included in this cross-sectional analysis; 29 with T2DM and obesity (T2DM-obesity), 53 with obesity without T2DM (obesity), and 17 controls without T2DM and obesity (controls). CYP activities were assessed after the administration of a cocktail of probe drugs including omeprazole (CYP2C19), midazolam (CYP3A), caffeine (CYP1A2), and losartan (CYP2C9). Jejunal and liver biopsies were also obtained to determine protein concentrations of the respective CYPs. CYP2C19 activity and jejunal CYP2C19 concentration were 63% (-0.39 [95% CI: -0.82, -0.09]) and 40% (-0.09 fmol/µg protein [95% CI: -0.18, -0.003]) lower in T2DM-obesity compared with the obesity group, respectively. By contrast, there were no differences in the in vivo activities and protein concentrations of CYP3A, CYP1A2, and CYP2C9. Multivariable regression analyses also indicated that T2DM was associated with interindividual variability in CYP2C19 activity, but not CYP3A, CYP1A2, and CYP2C9 activities. The findings indicate that T2DM has a significant downregulating impact on CYP2C19 activity, but not on CYP3A, CYP1A2, and CYP2C9 activities and protein concentrations in patients with obesity. Hence, the effect of T2DM seems to be isoform-specific.

Metacognitive strategy training versus psychoeducation for improving fatigue in children and adolescents with acquired brain injuries: A randomized controlled trial.

OBJECTIVE: The present study aims to explore the relative effectiveness of two group-based cognitive rehabilitation programs for reducing fatigue in pediatric acquired brain injury (pABI). METHOD: This is an exploratory study of secondary endpoints in a blinded, parallel-randomized controlled trial with children and adolescents (ages 10-17 years) with pABI and reported executive dysfunction. It investigates the effectiveness of a metacognitive program (pediatric goal management training, n = 36) compared to a psychoeducational program (pediatric brain health workshop, n = 37) for reducing fatigue (Pediatric Quality of Life Inventory, Multidimensional Fatigue Scale), 8 weeks and 6 months postintervention. RESULTS: Seventy-three participants completed the allocated interventions, and 71 attended the 6-month follow-up. The results showed a significant decrease in parent-reported fatigue for both interventions from baseline to the 6-month follow-up. Forty percent of the total sample had a reliable change. There was no significant difference between the intervention groups, but a tendency in favor of the psychoeducational approach. Only subscales cognitive and sleep/rest fatigue showed significant reductions. In regression analyses, several factors predicted fatigue at 6 months follow-up, but only better global outcome and executive attention predicted a decrease in fatigue symptoms after 6 months. CONCLUSIONS: Group-based cognitive rehabilitation in the chronic phase of pABI, including education of parents and teachers, may be helpful in reducing fatigue. Global outcome and executive attention at baseline predicted fatigue improvement. Developmental factors are important to consider when tailoring pediatric interventions, as well as modifiable factors associated with fatigue. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Alpha-2-adrenergic receptor agonists for the prevention of delirium and cognitive decline after open heart surgery (ALPHA2PREVENT): protocol for a multicentre randomised controlled trial.

INTRODUCTION: Postoperative delirium is common in older cardiac surgery patients and associated with negative short-term and long-term outcomes. The alpha-2-adrenergic receptor agonist dexmedetomidine shows promise as prophylaxis and treatment for delirium in intensive care units (ICU) and postoperative settings. Clonidine has similar pharmacological properties and can be administered both parenterally and orally. We aim to study whether repurposing of clonidine can represent a novel treatment option for delirium, and the possible effects of dexmedetomidine and clonidine on long-term cognitive trajectories, motor activity patterns and biomarkers of neuronal injury, and whether these effects are associated with frailty status. METHODS AND ANALYSIS: This five-centre, double-blind randomised controlled trial will include 900 cardiac surgery patients aged 70+ years. Participants will be randomised 1:1:1 to dexmedetomidine or clonidine or placebo. The study drug will be given as a continuous intravenous infusion from the start of cardiopulmonary bypass, at a rate of 0.4 µg/kg/hour. The infusion rate will be decreased to 0.2 µg/kg/hour postoperatively and be continued until discharge from the ICU or 24 hours postoperatively, whichever happens first.Primary end point is the 7-day cumulative incidence of postoperative delirium (Diagnostic and Statistical Manual of Mental Disorders, fifth edition). Secondary end points include the composite end point of coma, delirium or death, in addition to delirium severity and motor activity patterns, levels of circulating biomarkers of neuronal injury, cognitive function and frailty status 1 and 6 months after surgery. ETHICS AND DISSEMINATION: This trial is approved by the Regional Committee for Ethics in Medical Research in Norway (South-East Norway) and by the Norwegian Medicines Agency. Dissemination plans include publication in peer-reviewed medical journals and presentation at scientific meetings. TRIAL REGISTRATION NUMBER: NCT05029050.

Correlations between 4ß-hydroxycholesterol and hepatic and intestinal CYP3A4: protein expression, microsomal ex vivo activity, and in vivo activity in patients with a wide body weight range.

PURPOSE: Variability in cytochrome P450 3A4 (CYP3A4) metabolism is mainly caused by non-genetic factors, hence providing a need for accurate phenotype biomarkers. Although 4ß-hydroxycholesterol (4ßOHC) is a promising endogenous CYP3A4 biomarker, additional investigations are required to evaluate its ability to predict CYP3A4 activity. This study investigated the correlations between 4ßOHC concentrations and hepatic and intestinal CYP3A4 protein expression and ex vivo microsomal activity in paired liver and jejunum samples, as well as in vivo CYP3A4 phenotyping (midazolam) in patients with a wide body weight range. METHODS: The patients (n = 96; 78 with obesity and 18 normal or overweight individuals) were included from the COCKTAIL-study (NCT02386917). Plasma samples for analysis of 4ßOHC and midazolam concentrations, and liver (n = 56) and jejunal (n = 38) biopsies were obtained. The biopsies for determination of CYP3A4 protein concentration and microsomal activity were obtained during gastric bypass or cholecystectomy. In vivo CYP3A4 phenotyping was performed using semi-simultaneous oral (1.5 mg) and intravenous (1.0 mg) midazolam. RESULTS: 4ßOHC concentrations were positively correlated with hepatic microsomal CYP3A4 activity (ρ = 0.53, p < 0.001), and hepatic CYP3A4 concentrations (ρ = 0.30, p = 0.027), but not with intestinal CYP3A4 concentrations (ρ = 0.18, p = 0.28) or intestinal microsomal CYP3A4 activity (ρ = 0.15, p = 0.53). 4ßOHC concentrations correlated weakly with midazolam absolute bioavailability (ρ = - 0.23, p = 0.027) and apparent oral clearance (ρ = 0.28, p = 0.008), but not with systemic clearance (ρ = - 0.03, p = 0.81). CONCLUSION: These findings suggest that 4ßOHC concentrations reflect hepatic, but not intestinal, CYP3A4 activity. Further studies should investigate the potential value of 4ßOHC as an endogenous biomarker for individual dose requirements of intravenously administered CYP3A4 substrate drugs. TRIAL REGISTRATION: Clinical. TRIALS: gov identifier: NCT02386917.